This proposal is intended to study the basis of the antiproliferative actions of agents capable of interfering with polyamine metabolism and evaluate their ability to alter mitochondrial structure and function. Methylglyoxal-bis(guanylhydrazone), an agent used in the treatment of human leukemia, will be studied as an example of a potent inhibitor of spermidine biosynthesis. Other recently identified inhibitors of putrescine and spermidine biosynthesis will also be used. The objectives of this investigation are: 1) to clarify the basis for the cytotoxicity of the agents specifically interfering with polyamine metabolism in different normal and tumor cell types; 2) to evaluate the relationship, if any, between the changes in polyamine metabolism and changes in mitochondrial structure and function; 3) to utilize the basic information obtained to develop a test suitable for predicting sensitivity of individual patients with leukemia to methylglyoxal-bis(guanylhydrazone) and to improve selectivity of action of the drug; and 4) to assess the importance of polyamines as targets for cancer chemotherapy. Most of the basic in vitro work will be performed with mouse leukemia cells grown in culture. The work in vivo will be performed in syngeneic mice. The work involving human material will consist of in vitro studies on appropriate cell population derived from leukemia patients. Among the methods involved will be those used for cell growth, polyamine and ATP pool analysis, structural and functional alterations in mitochondria.